|
|
Home
Search
Study Topics
Glossary
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
||||||||||||||||||||||||||||||||||||
| Sponsor: | Vanderbilt University |
|---|---|
| Collaborators: |
University of Washington National Institutes of Health (NIH) |
| Information provided by (Responsible Party): | Alp Ikizler, Vanderbilt University |
| ClinicalTrials.gov Identifier: | NCT00878969 |
Purpose
The purpose of the study is to see how two classes of blood pressure medications,angiotensin-converting enzyme inhibitors (Ace inhibitors) and angiotensin receptor blockers (ARBs), differ in their long term effects on certain chemicals in the body and on the carotid arteries.
| Condition | Intervention | Phase |
|---|---|---|
|
Oxidative Stress Endothelial Dysfunction |
Drug: ramipril (ACE inhibitor) Drug: valsartan (ARB) Drug: Placebo |
Phase III |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Endpoint Classification: Pharmacokinetics Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor) Primary Purpose: Health Services Research |
| Official Title: | Genes, Fibrinolysis and Endothelial Dysfunction- Dialysis Aim 3 |
| Estimated Enrollment: | 210 |
| Study Start Date: | January 2010 |
| Estimated Study Completion Date: | December 2014 |
| Estimated Primary Completion Date: | December 2014 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Active Comparator: 1
If on a ACE or ARB,subjects will first undergo a three week washout period, the subjects will be randomized to take one of three treatments, ramipril, valsartan or placebo.
|
Drug: ramipril (ACE inhibitor)
Subjects will be randomized to ramipril 2.5 mg/d for one week followed by 5 mg/day for 18 months.
Other Name: Altace
|
|
Active Comparator: 2
If on a ACE or ARB,subjects will first undergo a three week washout period, the subjects will be randomized to take one of three treatments, ramipril, valsartan or placebo.
|
Drug: valsartan (ARB)
Subjects will be randomized to receive Valsartan 80 mg/d for one weeks followed by Valsartan 160 mg/d for 18 months
Other Name: Diovan
|
|
Placebo Comparator: 3
If on a ACE or ARB,subjects will first undergo a three week washout period, the subjects will be randomized to take one of three treatments, ramipril, valsartan or placebo.
|
Drug: Placebo
Subjects will be randomized to receive a placebo for 18 months
Other Name: Inactive pill
|
More than 400,000 individuals with chronic kidney disease undergo hemodialysis each year in the United States. Atherosclerotic cardiovascular disease is the leading cause of mortality in these patients. Conventional risk factors for CAD do not adequately explain this increased mortality, whereas biomarker of oxidative stress and inflammation correlate with clinical outcomes. Even with the use of biocompatible membranes, hemodialysis induces a systemic inflammatory reaction characterized by complement activation, leukocyte activation and the generation of reactive oxygen species and cytokines. Oxidative stress and inflammation promote endothelial dysfunction, a predictor of atherosclerotic cardiovascular events.
The purpose of the study is to test the hypothesis that angiotensin-converting enzyme inhibition and angiotensin receptor blockade differ in their long term effects on biomarkers of fibrinolysis, oxidative stress,inflammation and on carotid intima-media thickness (IMT), a predictor of cardiovascular events, in patients with chronic kidney disease undergoing maintenance hemodialysis.
Endogenous Bradykinin (BK) contributes to the hypotensive and pro-fibrinolytic effects of ACE inhibitors. It has been determined that endogenous BK contributes to the vasodilator effects of acute and chronic ACE inhibition. Studies have found that BK stimulates vascular t-PA release through a BK B2 receptor-dependent, NO and cyclooxygenase-independent pathway. Hemodialysis patients demonstrates endothelial dysfunction. Data suggests that t-PA release may be attenuated during stimulation of the endogenous kallikrein-kinin system by hemodialysis.
Intra-arterial infusion of BK increases vascular release of F2- isoprostanes, markers of oxidative stress, BK infusions also increase net release of the inflammatory cytokine IL-6. Preliminary data raise the possibility that activation of the endogenous kallikrein-kinin system during dialysis could promote inflammation in individuals with chronic kidney disease who are treated with an ACE inhibitor.
Cardiopulmonary bypass activates the endogenous kallikrein-kinin system and causes a systemic inflammatory response. Like hemodialysis, cardiopulmonary bypass activates the endogenous kallikrein-kinin system, increasing BK concentrations. In smokers, who like hemodialysis patients exhibit endothelial dysfunction, the t-PA response to BK was attenuated during cardiopulmonary bypass.
ACE inhibition enhances fibrinolysis and decreases inflammation following cardiopulmonary bypass. The short-term effect of both ACE inhibition and AT1 receptors on markers of fibrinolysis and inflammation during dialysis are currently being studied.
Circulating BK concentrations are increased during hemodialysis in individuals treated with an ACE inhibitors compared to those treated with an AT1 receptor blocker.
Bradykinin receptor blockade and the fibrinolytic and inflammatory response to hemodialysis. It is hypothesized that subjects with CAD, the t-PA response to hemodialysis will be blunted compared to that measured in subjects without evidence of CAD, whereas the inflammatory response wil be similar or enhanced.
Eligibility| Ages Eligible for Study: | 18 Years and older |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | Yes |
Inclusion Criteria:
Exclusion Criteria:
Contacts and Locations| Contact: Delia M Woods, BSN | 615-322-3371 | delia.woods@vanderbilt.edu |
| United States, Tennessee | |
| Vanderbilt University Medical Center | Recruiting |
| Nashville, Tennessee, United States, 37232 | |
| Contact: Nancy J Brown, MD 615-343-8701 nancy.j.brown@vanderbilt.edu | |
| Contact: Jorge Gamboa, MD, PhD 615-343-6479 jorge.gamboa@vanderbilt.edu | |
| Principal Investigator: Nancy J Brown, MD | |
| Principal Investigator: Talat A Ikizler, MD | |
| Sub-Investigator: Jorge Gamboa, MD, PhD | |
| Principal Investigator: | Nancy J Brown, MD | Vanderbilt University |
| Principal Investigator: | Talat A Ikilzer, MD | Vanderbilt University |
| Principal Investigator: | Jonathan Himmelfarb, MD | University of Washington |
More Information
| Responsible Party: | Alp Ikizler, Professor, Vanderbilt University |
| ClinicalTrials.gov Identifier: | NCT00878969 History of Changes |
| Other Study ID Numbers: | Fibrinolysis in Dialysis Aim 3, R01 HL065193-08A2 |
| Study First Received: | April 8, 2009 |
| Last Updated: | January 9, 2012 |
| Health Authority: | United States: Institutional Review Board |
|
Hemodialysis fibrinolysis oxidative stress systemic inflammatory reaction |
endothelial dysfunction carotid intima media thickness (IMT angiotensin receptor blockade angiotensin converting enzyme inhibition |
|
Angiotensin-Converting Enzyme Inhibitors Ramipril Valsartan Protease Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action |
Pharmacologic Actions Antihypertensive Agents Cardiovascular Agents Therapeutic Uses Angiotensin II Type 1 Receptor Blockers Angiotensin Receptor Antagonists |
